Neuropeptide Y1 Receptor NPY1RDiscovery of Naturally Occurring Human Genetic Variants Governing Gene Expression In Cella as Well as Pleiotropic Effects on Autonomic Activity and Blood Pressure In Vivo
Lei Wang, MD*,
Fangwen Rao, MD*,
Kuixing Zhang, MD, PhD*,
Manjula Mahata, PhD*,
Juan L. Rodriguez-Flores, PhD*,
Maple M. Fung, MD*, ,
Jill Waalen, MD ,
Myles G. Cockburn, PhD||,
Bruce A. Hamilton, PhD*,
Sushil K. Mahata, PhD*, and
Daniel T. O'Connor, MD*, ,,*
* Department of Medicine, University of California at San Diego, California
Department of Pharmacology, University of California at San Diego, California
VA San Diego Healthcare System, San Diego, California
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California
|| Department of Preventive Medicine, USC Keck School of Medicine, Los Angeles, California
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Figure 1 NPY1R Resequencing Strategy and Identified Variants
Sequences conserved between mouse and human neuropeptide Y1 receptors (NPY1R) were visualized with Windows VISTA (Microsoft, Redmond, Washington). Locations of common (minor allele frequency >5%) and rare single nucleotide polymorphisms (SNPs) are indicated. Positions are numbered upstream or downstream of the transcriptional initiation (exon 1) start site. Solid blocks = open reading frame; hatched blocks = untranslated regions (UTRs). PCR = polymerase chain reaction.
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Figure 2 NPY1R 3'-UTR Variant A+1050G: Pleiotropic Effects on Coupling Between Baroreceptors and Stress Response
BP = blood pressure; GEE = generalized estimating equation; other abbreviations as in Figure 1.
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Figure 3 NPY1R Common Variants in the 3'-UTR (A+1050G) and Proximal Promoter (A-585T) Influence BP Both Independently and Interactively
ANOVA = analysis of variance; BP = blood pressure; DBP = diastolic blood pressure; other abbreviations as in Figure 1.
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Figure 5 NPY1R 3'-UTR Polymorphism A+1050G Influences Gene Expression In Cella
Results of luciferase reporter/3'-UTR variant transfections into PC12 cells are shown. Abbreviations as in Figure 1.
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Figure 6 Effect of NPY1R Common Promoter Variants (A-585T and Ins/Del) on Gene Expression In Cella
Natural: Haplotype combination found in human NPY1R promoter deoxyribonucleic acid. Del = deletion; Ins = insertion; other abbreviations as in Figure 1.
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Figure 7 NPY1R 3'-UTR Variant A+1050G Occurs in a Micro-RNA Recognition Motif
(A, B) Complementarity between hsa-miR-511 and the NPY1R 3'-UTR site (1034–1055 bp downstream from the NPY1R stop codon), variant (A) versus wild-type (B). The A+1050G SNP is given in bold type. Upper case: maximal scoring alignment region. Lowercase: not part of maximal scoring alignment region. (C, D) Hybridization of miR-155 to the NPY1R mRNA harboring the A (D) or G (C) alleles at A+1050G. Arrows highlight the polymorphic site. Calculated mfe= minimum free energy. Abbreviations as in Figure 1.
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Figure 8 Neuropeptide Y Type 1 Receptor
Transcriptional/translational, physiological, and disease consequences of common genetic variation in the 3'-UTR and promoter. Abbreviations as in Figure 1.
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+1050G) Is Associated With Both DBP and SBP in a European Ancestry Population